Optimal clinical management of children getting dietary therapies for epilepsy: Updated suggestions of the International Ketogenic Diet Study Group Kossoff et al. In the former approach, the patient must be hospitalized for 12-48 h, or when ketones are present in the urine Rubenstein,to prevent the development of dehydration and hypoglycemia.
This method tends to accelerate the development of ketosis although it can generate more stress on the patient Armeno et al. When ketosis is reached, the meals are calculated to maintain a continuous KD ratio, while calories are added until full-calorie meals are tolerated Kossoff et al. The latter approach requires no hospitalization and the KD ratio increases weekly, fromand to Bergqvist et al. Most of the literature suggests that there is no significant difference between the two approaches with regards to the time needed to reach ketosis and the occurrence of hypoglycemia Kim et al.
Taking into account that the KD provides only small amounts of fruits, vegetables, grains, cheese and milk, supplementation is essential. Low-carbohydrate multivitamin and mineral supplements should daily be taken. Follow Up Patients on the KD should be seen every 3 months regularly, and the family should be able to easily contact the diet team to resolve possible doubts and discuss adverse effects. It has been noted that it is possible to enhance the cognitive development and behavior even without a change in the seizure frequency.
Although some authors have reported no relationship between the efficacy and the known level of ketosis, a week Kossoff et al it is still recommended to measure the urine ketosis several times. For efficacy, the KD requires a period of at least 3 months from the right time that the patient reaches ketosis, so it is important to motivate the patient and the family to continue with the diet for this period without changing the medication.
Acute AE include dehydration, hypoglycemia, lethargy, metabolic acidosis, and gastrointestinal symptoms. However, most of the relative side effects involve weight loss, high levels of low-density lipoprotein, and elevated total cholesterol Liu et al. Other important AE are gastrointestinal symptoms, which include constipation, diarrhea, vomiting, and stomach pain. The family should also be informed about how exactly to recognize the symptoms of hypoglycemia and be advised to administer a little amount of juice or other kinds of dextrose Kossoff et al.
Nephrolithiasis may develop, and an stomach ultrasonography should be requested. Mechanism of Action The understanding of the mechanisms of action of KD is incomplete; however, some theories have been advanced about how exactly it modifies the neuronal metabolism and excitability in order to reduce the seizure frequency. Possibly, the real mechanism of reduction of cortical hyperexcitability involves multiple factors.
Some of the systems involved in seizure reduction are related to metabolic changes in the blood and cerebrospinal fluid CSFincluding a decrease in glucose levels and an increase in KB. The mitochondria function and energy reserve may play a role in the KD mechanisms also, resulting in synapse stabilization and excitatory decrease.
There are many theories about the role of KB, but the existence of an anticonvulsant effect is controversial. Some authors have found no relationship between KB and synaptic seizure and transmission control. Experimental studies in an animal model showed that in rats exposed to KD there was no change in synaptic plasticity, using paired-pulse modulation and long-term potentiation Thio et al. Similarly, Likhodii et al. In epileptic Kcna1-null mice spontaneously, KB supplementation resulted in attenuation of electrographic seizure-like events Kim et al.
These authors also observed an inhibitory effect of KB on mitochondrial permeability transition related to necrotic and apoptotic death. Moreover, in experimental models, acetoacetate exerted a broad-spectrum anticonvulsant effect Rho et al. Similarly, to these scholarly studies, injection of KB led to the reduction of seizure susceptibility Gasior et al. Ma et al. In addition, KB can exert a direct inhibitory effect on the vesicular glutamate transport Juge et al.
It is possible that these divergent results are related to the various concentrations of KB used in these studies and the different seizure thresholds of the animal models. These conflicting results can be also explained by distinctions in diet composition. Neuronal Metabolism and Synaptic Function Another hypothesis about the function of the KD is related to changes in neuronal metabolism, mitochondrial function and energy reserve, and the environment.
In normal conditions, the usual substrate for the neurons is glucose. To facilitate its diffusion through the brain-blood barrier, glucose transports are present in the brain capillary endothelial layer Greene et al. The glucose metabolism produces the available energy that is necessary for seizure activity rapidly. Therefore, in patients on the KD, the blood glucose energy levels are low, and the brain starts to use KB for energy. This anaerobic metabolism slows the energy availability, which reduces seizures.
The anticonvulsant propriety of a decrease in glucose metabolism has been proven in experimental models in which the administration of 2-Deoxy-D-glucose elevates the seizure threshold Garriga-Canut et al. The anticonvulsant effect of the KD can be reversed after glucose infusion Huttenlocher quickly, Based on these data, we can postulate the influences not only of the KB, as discussed above, but also the reduction in glucose levels as a mechanism of action of the KD.
Chronic ketosis might play a role in the KD anticonvulsant properties, since it has been proven that chronic ketosis elevates the brain energy reserve via stabilization and reduction of excitability of synapses Devivo et al. The energy reserve is associated with mitochondria, which is a significant component to consider in the antiepileptic effect of KD. Bough et al. The increase in mitochondrial metabolism leads to an increase in ATP production, which activates KATP, in turn attenuating neuronal excitability.
This activation could be associated with adenosine A1 receptors Li et al. In this process, we can postulate that modifications of the metabolism are associated with an increase of ATP, and improve mitochondrial cell and capacity energy, with an increase in metabolic resilience.
Neurotransmitter Function The KD-induced synaptic stabilization is additionally related to changes in critical amino acids because of this of ketone metabolism. It has been proposed that KD interferes with the concentration of gamma-aminobutyric acid GABAthe major inhibitory neurotransmitter. This occurs due to the inhibitory effect of aspartate on glutamate decarboxylase and the facilitation of the conversation of glutamate to glutamine in the astrocytes Yudkoff et al.only can GABA be increased
Not, but also other neurotransmitters such as adenosine A1 can be implicated in the anti-seizure effect of the KD Szot et al. However, more evidence is needed. Gut Microbiota, Inflammation, and Genetic The role of gut microbiota has been studied for its effect on several diseases recently, those with some inflammatory involvement especially.
Several metabolic pathways are known to be modulated by the gut microbiota. Olson et al. She found that KD modifies the gut microbiota, with a decrease in increases and alpha-diversity in the putatively beneficial bacteria Akkermansia muciniphila and Parabacteroides spp. This microbiota transformation leads to changes in the colonic luminal metabolome, with a decrease in gamma-glutamyl amino acids. In an acute electroshock model, it is reported that KD confers protection against seizures.
Moreover, KD decreases the frequency of spontaneous seizures in Kcna1 knockout mice Kim et al. In summary, changes in the gut microbiota appear to be important for the KD-mediated seizure protection. The role of inflammatory cytokines in epilepsy is well known, and there is evidence that KD interferes with pro-inflammatory cytokines. Dupuis et al. Notably, there is a relationship between epigenetic and metabolic modifications.
Shimazu et al. This total result emphasizes that the KD has a potential role as a disease-modifying treatment in epilepsy. In conclusion, all the mechanisms described above result in systemic modifications and a dynamic metabolic homeostasis, in which the interplay among KB, glucose levels, mitochondrial function, synaptic neurotransmitters, and channel modifications can result in changes in the seizure hyperexcitability and threshold.
These changes contribute to the final antiseizure mechanism of KD. Multiple mechanisms of action might describe why the modification of the KD can be effective even without ketosis. Importantly, the KD systemic action can have a broad spectrum of effects that may be beneficial in the treatment of different types of epilepsy and associated comorbidities such as cognition impairment, psychiatric disturbance, and sudden unexplained death.
Because of carbohydrate restriction, the MAD can produce urinary ketones Carrette et al also. The MAD does not require weighing food on a gram scale, or restriction of calories, liquids or protein, and may be a good option for patients who are unable to tolerate a more restrictive diet like the classical ketogenic diet KD Cervenka et al.
Low-carbohydrate calcium and multivitamin carbonate supplementation is recommended in the MAD Kossoff et al. Efficacy in Children Several studies have proven that the MAD, besides being more palatable, is as effective as the KD in the treatment of drug-resistant epilepsy in children Miranda et al. Treatment with MAD was proven to be more effective in seizure control when the MAD was started with lower carbohydrate limits Kossoff et al. Efficacy in Adolescents and Adults The efficacy of the MAD is also verified for the treatment of drug-resistant epilepsy in adults and adolescents.
In a recent meta-analysis, eight studies were determined that used the MAD in adult patients with refractory epilepsy, aged between 15 and 86 years, with treatment times ranging from 3 to 36 months. The rate of abandonment of the diet varied between Side Effects The MAD has been proven to be better tolerated than the classical KD, but some typical side effects such as gastrointestinal complaints, weight and dyslipidemia loss are reported Zare et al.
Beneficial effects have been reported also, such as mood improvement Carrette et al. This alternative diet treatment is based on a ratio 0. The tendency is measured by The GI of a food to raise the blood glucose levels, compared to an equivalent amount of the reference carbohydrate, glucose Pfeifer et al usually.
Compared to classic the KD, the LGIT produces a smaller increase in ketone body levels, but has comparable efficacy, better tolerability and easier implementation Thiele and Pfeifer, ; Pfeifer et al. Efficacy The LGIT has verified to be effective in the treatment of focal and generalized epilepsies, with a reduction in seizure frequency occurring at 3-14 months and seizure control continuing for at least 1 year after the end of treatment Pfeifer et al.
Pfeifer and Thiele reported the use of LGIT in 20 drug-resistant epilepsy patients aged 5 to 34 years. Coppola et al. However, according to a recent systematic review, the positive results for LGIT efficacy in epileptic patients are doubtful due to the low number of high-quality studies. In this review, which included all electronic literature databases until Julythe authors found only eight studies with good or fair quality Conclusion The CKD and its variants should be considered as an alternative for non-surgical pharmacoresistant patients with epilepsy, of any age.
Each patient must have an designed diet; however, adult patients have more difficulty in maintaining the CKD. It is essential to inform the patient and the grouped family about the efficacy and AE related to the KD, and the use of websites and videos may help in this education.
Although several theories exist about the mechanisms of action, further study is needed even so the positive results are probably due to several mechanisms. Author Contributions All the authors contributed to the writing and revising of the manuscript substantially. Conflict of Interest Statement The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
References Armeno M. Ketogenic diet treatment of epilepsy in adults. Fasting versus gradual initiation of the ketogenic diet: a prospective, randomized clinical trial of efficacy. Epilepsia 46 – Energy metabolism as part of the anticonvulsant mechanism of the ketogenic diet.